Lifelong highly active antiretroviral therapy (HAART) not only presents formidable problems in terms of patient management, cost and long-term toxicities but also fails to eradicate the virus from infected individuals. HIV persists in the face of HAART due to constitutive low-level replication in sites that are poorly accessible to drugs and the development of latent infections in a variety of types including the long-lived memory CD4+ T cell population, macrophages, and microglial cells in the brain. The need to develop novel therapeutic tools to attack the latently infected population has been widely recognized, but there has been little progress using conventional drug development approaches. Here we propose to develop novel technologies allowing exploitation a natural epigenetic silencing mechanism, DNA methylation, to block HIV transcription. As a prelude to developing therapeutic silencing agents, a much better understanding of the natural silencing mechanisms used by cells to control retroviruses and retrotranspons is needed. Key questions about HIV silencing that remain to be answered include: What are the primary sequence triggers and mechanisms that induce silencing (i.e. protein repressors and/or viral-derived siRNA)? What conditions lead to proviral DNA methylation? Do similar silencing mechanisms operate in each of the cell types infected by HIV? Do drugs of abuse block HIV silencing by inducing histone acetylation? Therapeutic approaches to exploit silencing include development of small molecules that enhance DNA methylation, gene-specific induction of silencing by short double-stranded RNA (or it analogues) and silencing by direction of DNA methyltransferases to promoters through protein mediators. In contrast to traditional antivirals, which require continuous administration, therapeutic epigenetic gene silencing has the potential to produce stable inheritable blocks to viral replication after only a single exposure of an infec